Therapeutic agents for treating peptic ulcer have been developed based on two main modes of action—i.e., regulation of aggressive factors and enhancement of defensive factors. Development has been particularly focused on the regulation of aggressive factors. Development on the regulation of aggressive factors has evolved from the use of antacids to anti-cholinergic drugs and H2 receptor antagonists, and recently to proton pump inhibitors (PPI), which are the leading products in the current market.
Since the discovery of highly concentrated HCl secretion in mucosal membranes by Prout in 1884, the mechanism of acid secretion has been actively studied for almost a century. Initially, Belladonna, the first antiulcer drug, was used, followed by anti-cholinergic drugs. In 1920, it was found that antacid secretion is stimulated by histamine. In 1977, Cimetidine (Tagamet®) was developed as the first histamine H2 receptor antagonist which inhibits the action of histamine, a strong gastric acid-secreting hormone, at H2 receptor. Since then, various drugs which antagonize receptors for several stimulants of acid secretion have been developed, and histamine H2 receptor antagonists, such as Ranitidine (Zantac®(developed in 1981) and Famotidine (Gaster®/Pepcid®)(developed in 1985) now occupy most of the global peptic ulcer drugs market. Additionally, since the first isolation of Helicobacter pylori as a pathogen causing gastritis and gastric ulcer in 1983, combination therapies consisting of proton pump inhibitors or H2 receptor antagonists and chemotherapeutics for eradication of Helicobacter pylori have been developed.
Recently, there has been a growing need for the development of a proton pump inhibitor with a reversible inhibition mechanism, and global pharmaceutical firms are actively involved in the research. To be distinguishable from conventional PPI drugs, represented by Omeprazole, the reversible proton pump inhibitors are called as potassium competitive acid blockers (P-CAB) or acid pump antagonists (APA).
Meanwhile, the H+ secretion pathway in the gastric parietal cells was not identified for a long time until it was recently discovered that H+ secretion in the gastrointestinal tract involves an action of H+/K+-ATPase in the microsomal fraction from the gastric parietal cells for the exchange of H+ and K+, and H+/K+-ATPase was then termed a “proton pump”. H+/K+-ATPase uses the energy obtained by the decomposition of ATP, abundant in mitochondria, to secrete H+ derived from H2O decomposition into the gastric cavity in vivo. Here, the exchange between K+ and H+ occurs at a ratio of 1:1, and it was confirmed that H+/K+-ATPase is present in many H+-secreting animals as well as in humans.
In other words, various acid-secretion stimulants (histamine, acetylcholine, gastrin, etc.) bind to receptors present in the cell membrane of the gastric parietal cells and thereby cause a series of reactions for gastric acid secretion, and in its final step, H+/K+-ATPase, a proton pump, operates to release H+ and absorb K+ in the gastric parietal cells. Accordingly, compounds which can prevent gastric acid secretion by inhibiting the proton pump in the final step of gastric acid secretion have no anti-cholinergic action or H2 receptor antagonistic action. In particular, they are absorbed into the body in the form of an inactive pro-drug and are densely distributed within the secretory canaliculi of parietal cells in gastric mucosa, i.e., the unique acidic compartments in the human body, and are then activated to inhibit the proton pump in the final step of gastric acid production, thereby inhibiting gastric acid secretion in a unique and selective manner.
Examples of the representative drugs developed for the purpose of inhibiting the proton pump include Omeprazole, Lansoprazole, Pantoprazole, Esomeprazole, etc. These drugs have stronger and more sustained inhibition activity against gastric acid secretion than conventional drugs and are thus widely used as therapeutics for the treatment of peptic ulcer. Additionally, Omeprazole-based compounds exhibit a dual characteristic of both aggressive and defensive actions with strong inhibition of gastric acid secretion and gastric membrane protection activity (cytoprotective activity) at the same time. As compared with H2 receptor antagonists, these compounds exhibit a stronger acid inhibition during daytime as well as at night, and also have a low recurrence rate of peptic ulcer.
However, a proton pump inhibitor with an irreversible action mechanism, due to its long-term inhibition of gastric acid secretion in the stomach, can cause gastric bacteria proliferation, promotion of proton pump expression, and tumorigenesis induced by increased gastrin levels. Accordingly, in order to overcome the above problems, research has been focused on the development of a reversible proton pump inhibitor capable of inhibiting the secretion of gastric acid only for a particular period of time from administration of a drug. So far, revaprazan (Revanex®) released by Yuhan Corp. (Korea) on January 2007 is the only drug, but more novel drugs are expected to enter the market because major global pharmaceutical firms have been conducting research efforts to develop anti-peptic ulcer drugs which are capable of functioning as reversible proton pump inhibitors.
Examples of representative proton pump inhibitors include a pyrrole derivative disclosed in International Publication No. WO2007/026916 (Takeda Pharmaceutical Co. Ltd.), a pyrrolo[2,3-c]pyridine derivative disclosed in International Publication No. WO2006/025716 (Yuhan Corp.), and a benzimidazole derivative disclosed in International Publication No. WO2007/072146 (Pfizer Inc., Japan; Raqualia Pharma Inc.).